Reducing fatty acid oxidation improves cancer-free survival in a mouse model of Li-Fraumeni syndrome

Ping Yuan Wang, Jin Ma, Jie Li, Matthew F. Starost, Michael J. Wolfgang, Komudi Singh, Mehdi Pirooznia, Ju Gyeong Kang, Paul Mingyou Hwang

Research output: Contribution to journalArticlepeer-review

Abstract

Germline mutations of TP53, which cause the cancer predisposition disorder Li-Fraumeni syndrome (LFS), can increase mitochondrial activity as well as fatty acid β-oxidation (FAO) in mice. Increased fatty acid metabolism can promote cancer malignancy, but its specific contribution to tumorigenesis in LFS remains unclear. To investigate this, we crossed LFS mice carrying the p53 R172H knock-in mutation (p53172H/H, homolog of the human TP53 R175H LFS mutation) with myoglobin-knockout (MB-/-) mice known to have decreased FAO. MB-/- p53172H/H double-mutant mice also showed mildly reduced FAO in thymus, a common site of T lymphoma development in LFS mice, in association with an approximately 40% improvement in cancer-free survival time. RNA sequencing profiling revealed that the p53 R172H mutation promotes mitochondrial metabolism and ribosome biogenesis, both of which are suppressed by the disruption of MB. The activation of ribosomal protein S6, involved in protein translation and implicated in cancer promotion, was also inhibited in the absence of MB. To further confirm the role of FAO in lymphomagenesis, mitochondrial FAO enzyme, carnitine palmitoyltransferase 2 (CPT2), was specifically disrupted in T cells of p53172H/H mice using a Cre-loxP-mediated strategy. The heterozygous knockout of CPT2 resulted in thymus FAO haploinsufficiency and an approximately 30% improvement in survival time, paralleling the antiproliferative signaling observed with MB disruption. Thus, this study demonstrates that moderating FAO in LFS can suppress tumorigenesis and improve cancerfree survival with potential implications for cancer prevention.

Original languageEnglish (US)
Pages (from-to)31-40
Number of pages10
JournalCancer Prevention Research
Volume14
Issue number1
DOIs
StatePublished - Jan 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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